Sekar Kathiresan (Verve)

Sekar Kathire­san show­cas­es his­toric mon­key da­ta in hunt for a once-and-done gene edit­ing ap­proach to pre­vent heart at­tacks

In a first for CRISPR — a field that’s seen quite a few his­toric moves in the past cou­ple of years — sci­en­tists have slashed cho­les­terol and lipid lev­els in mon­keys us­ing a tech­nique known as base edit­ing, gen­er­at­ing cru­cial proof-of-con­cept for both the biotech be­hind the ex­per­i­ment and a key part­ner.

Verve Ther­a­peu­tics de­signed two sim­i­lar ex­per­i­ments to test whether they can re­pro­duce pro­tec­tive mu­ta­tions in a pair of genes us­ing an ade­nine base ed­i­tor, which pre­cise­ly al­ters a cho­sen A to a G in the genome. CEO and co-founder Sekar Kathire­san pre­sent­ed the re­sults at a vir­tu­al keynote for the In­ter­na­tion­al So­ci­ety for Stem Cell Re­search over the week­end.

The base ed­i­tors ap­peared to have es­sen­tial­ly turned off genes, shut­ting down pro­duc­tion of cor­re­spond­ing pro­teins. That trans­lat­ed to a 60% drop in LDL with the PC­SK9 ther­a­py and a 64% plunge in triglyc­erides on the ANGPTL3 treat­ment.

When it comes to low­er­ing the col­lo­qui­al bad cho­les­terol, “60% is on par if not bet­ter than any oth­er treat­ment out there,” Kathire­san told End­points News just af­ter his pre­sen­ta­tion.

These re­sults are the cul­mi­na­tion of Kathis­er­an’s decades-long search for ge­net­ic clues for solv­ing coro­nary heart dis­ease, the lead­ing cause of death in the world. While di­rec­tor of the Cen­ter for Ge­nom­ic Med­i­cine at Mass­a­chu­setts Gen­er­al Hos­pi­tal and the Car­dio­vas­cu­lar Dis­ease Ini­tia­tive at the Broad In­sti­tute, he and col­leagues had iden­ti­fied eight genes that har­bor rare mu­ta­tions as­so­ci­at­ed with re­sis­tance to my­ocar­dial in­farc­tion. Af­ter show­ing in mice that they could ad­min­is­ter a one-time treat­ment for per­ma­nent low­er­ing of cho­les­terol, he left acad­e­mia to work on bring­ing it to hu­mans full-time.

There is, of course, still a long way to go. But Kathire­san be­lieves the new da­ta have lit up Verve’s path to the clin­ic.

They are still choos­ing be­tween the PC­SK9 and ANGPTL3 pro­grams as their lead can­di­date. Once they do — the dead­line will be the end of the year — an IND for pa­tients ge­net­i­cal­ly pre­dis­posed to high risk of heart at­tack is in sight for 2022.

Both pro­grams demon­strat­ed dra­mat­ic re­duc­tions in the tar­get pro­tein, cut­ting 89% of PC­SK9 and 95% of ANGPTL3 from the blood­stream. With the study lim­it­ed to two weeks, though, the dura­bil­i­ty ques­tions loomed large dur­ing the Q&A.

“We have en­cour­ag­ing da­ta out to sev­er­al months now,” Kathire­san said, ex­press­ing con­fi­dence that the edit­ing will be sta­ble long-term.

The rate of DNA reached 67% of the liv­er for PC­SK9 and 60% for ANGPTL3 which, Kathis­er­an point­ed out, rep­re­sents the ma­jor­i­ty of he­pa­to­cytes as around 30% of the liv­er is sup­port­ing tis­sue. Get­ting to not just ma­ture he­pa­to­cytes but al­so stem cells would be cru­cial. In pre­vi­ous re­search by oth­er groups, sci­en­tists have ob­served con­tin­ued edit­ing in mice cells even when they chop out parts of the liv­er and let it re­gen­er­ate.

Con­sid­er­ing the base ed­i­tors were de­ployed in vi­vo, safe­ty was al­so para­mount. Verve re­port­ed no off-tar­get ed­its in the 108 sites mea­sured — ow­ing, Kathire­san said, to the tech­nol­o­gy they have li­censed from Beam Ther­a­peu­tics.

Un­like the first gen­er­a­tion of CRISPR edit­ing, base edit­ing doesn’t snip at the site Cas9 brings it to; rather, through an en­zyme, it con­verts one base to an­oth­er chem­i­cal­ly.

“So it’s kind of in­ge­nious be­cause it us­es the GPS lo­cal­iza­tion fea­ture of Cas9, but it doesn’t use the dou­ble-strand break fea­ture of Cas9,” he said.

Apart from the mR­NA that forms the ed­i­tor, every Verve ther­a­py al­so con­sists of a guide RNA — picked out from hun­dreds — di­rect­ing the ma­chin­ery to the de­sired spot, all en­cap­su­lat­ed in a lipid nanopar­ti­cle en­gi­neered in col­lab­o­ra­tion with Van­cou­ver-based Acuitas.

De­liv­er­ing with lipid nanopar­ti­cles in­stead of a vi­ral vec­tor is a de­lib­er­ate choice.

“We need to get in, get the ed­i­tor and the guide RNA, get the edit­ing to hap­pen and then every­thing to go away as quick­ly as pos­si­ble,” Kathire­san said, “be­cause the longer the liv­er is ex­posed to the edit­ing ma­chin­ery, the more like­ly you are to get off-tar­get ef­fects. and lipid nanopar­ti­cles al­low de­liv­ery and then res­o­lu­tion of the process with­in a cou­ple of days.”

Al­so de­lib­er­ate is their de­ci­sion to part­ner wide­ly and as­sem­ble — not in­vent — all the tools that might aid their work. Base ed­i­tors aren’t go­ing to cov­er the full spec­trum of pos­si­ble and nec­es­sary changes as Kathire­san and his team go down their pri­or­i­tized list of eight genes. But they are tak­ing it one step at a time.

Da­ta Lit­er­a­cy: The Foun­da­tion for Mod­ern Tri­al Ex­e­cu­tion

In 2016, the International Council for Harmonisation (ICH) updated their “Guidelines for Good Clinical Practice.” One key shift was a mandate to implement a risk-based quality management system throughout all stages of a clinical trial, and to take a systematic, prioritized, risk-based approach to clinical trial monitoring—on-site monitoring, remote monitoring, or any combination thereof.

Pfiz­er's big block­buster Xel­janz flunks its post-mar­ket­ing safe­ty study, re­new­ing harsh ques­tions for JAK class

When the FDA approved Pfizer’s JAK inhibitor Xeljanz for rheumatoid arthritis in 2012, they slapped on a black box warning for a laundry list of adverse events and required the New York drugmaker to run a long-term safety study.

That study has since become a consistent headache for Pfizer and their blockbuster molecule. Last year, Pfizer dropped the entire high dose cohort after an independent monitoring board found more patients died in that group than in the low dose arm or a control arm of patients who received one of two TNF inhibitors, Enbrel or Humira.

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Steve Harr (L) and Hans Bishop

One of the most am­bi­tious start­up teams in biotech just out­lined plans for a $400M IPO and a val­u­a­tion of about $4B

The executive team at Sana Biotechnology has sketched out more details about the full scope of its ambitions as the new unicorn to watch. They amended their S-1 today to include a price range of $20 to $23 a share — which puts them in reach of pulling in around $400 million on the high end with a market value starting right around $4 billion.

That’s not bad for a preclinical biotech with no drugs yet in human studies, but it squares with its ambitions to remake the cell therapy field with a slate of in-house platforms. The biotech raised $705 million — primarily from ARCH (44 million shares) and Flagship (34.2 million shares) — to get to this stage.

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Lil­ly at­tempts to re­vive an old idea for tack­ling pain, li­cens­ing PhI pro­gram from Japan’s Asahi Ka­sei Phar­ma

Eli Lilly is fronting some new cash in a space they’re quite familiar with.

The company is partnering with Japan’s Asahi Kasei Pharma on an experimental drug for chronic pain, acquiring the rights for the P2X7 receptor antagonist program dubbed AK1780. Lilly will shell out a pretty penny for the program, promising up to $410 million total should each milestone payment come to pass.

Asahi Kasei will receive an upfront sum of $20 million for the candidate. In addition, Lilly is on the hook for up to $210 million in development and regulatory milestones and another potential $180 million in sales milestones. Asahi Kasei can also obtain royalties ranging from the mid-single to low-double digits should an approved product come out of the deal.

Ther­mo Fish­er plat­form seeks to ex­pe­dite donor cell cul­ti­va­tion for al­lo­gene­ic cell ther­a­pies

One of the world’s leading CDMOs has launched a new technology it says will expedite a quickly-growing sect of biotech drug development: off-the-shelf, allogeneic cell therapies.

It’s been nearly a decade since the FDA approved the first use of the method that uses healthy donor cells to create a master cell bank, which is then used for specific therapies — a cord blood allogeneic treatment called Hemacord. In the years since, the use of allogeneic cells has taken off in research circles, most notably in the use of T cell therapies to target solid tumor cancers.

Top gene ther­a­py deals, M&A pacts in 2020 high­light an­oth­er big year in one of the hottest fields in bio­phar­ma

Chris Dokomajilar at DealForma has been crunching the numbers on gene therapy deals over the last 2 years and came away with a few key observations.

Both the upfront cash and deal totals last year backed off a bit from the record high hit in 2019, but the totals are still running well ahead of anything we’ve seen in the years prior to 2019/2020.
2020 R&D partnerships came in at 23 deals, with $1.1 billion in disclosed upfront cash and equity and more than $8.5 billion in total deal value. Looking at 2019-2020 M&A, Dokomajilar found: 9 Acquisitions, with over $11.1 billion in disclosed upfront cash and equity and more than $13.4 billion in total M&A value.

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Covid-19 roundup: EU and As­traZeneca trade blows over slow­downs; Un­usu­al unions pop up to test an­ti­bod­ies, vac­cines

After coming under fire for manufacturing delays last week, AstraZeneca’s feud with the European Union has spilled into the open.

The bloc accused the pharma giant on Wednesday of pulling out of a meeting to discuss cuts to its vaccine supplies, the AP reported. AstraZeneca denied the reports, saying it still planned on attending the discussion.

Early Wednesday, an EU Commission spokeswoman said that “the representative of AstraZeneca had announced this morning, had informed us this morning that their participation is not confirmed, is not happening.” But an AstraZeneca spokesperson later called the reports “not accurate.”

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Bob Nelsen (Michael Kovac/Getty Images)

ARCH an­nounces largest fund yet, rais­ing $1.85B to back men­tal health, cell and gene edit­ing ap­proach­es

Nearly a year ago, as the pandemic encroached and the stock market cratered, Flagship and ARCH Venture announced three mega-funds worth a combined $2.6 billion. They wanted, ARCH’s Bob Nelsen said, to restore confidence “that there was money out there and a lot of it” to invest in biotech.

Since then, the stock market has returned — almost frighteningly so — and Nelsen has kept raising and spending cash. On Thursday, he announced a new fund, worth $1.85 billion. It’s the largest pot yet for a VC famous for its deep pockets.

Janet Woodcock (AP Images)

Ad­vo­ca­cy groups don't want Janet Wood­cock to head the FDA, blast­ing ‘reg­u­la­to­ry fail­ures’ in opi­oid cri­sis

It turns out the controversies around Janet Woodcock’s regulatory legacy weren’t limited to Sarepta’s eteplirsen.

A coalition of advocacy groups dedicated to the opioid crisis urged Norris Cochran and Xavier Becerra — the acting and designated HHS secretary, respectively — to keep her reign as interim FDA chief a “very short transition.” During her lengthy tenure as CDER, they add, Woodcock presided over “one of the worst regulatory agency failures in U.S. history.”

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